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来自MASLD患者的iPSC衍生的肝细胞表现出早期的线粒体功能障碍

Dounia Le Guillou, Kevin Siao, Chris L Her

bioRxiv : the preprint server for biology

|September 5, 2025

概括

与代谢功能失调相关的脂肪性肝病 (MASLD) 患者的细胞显示线粒体受损. 当这些细胞分化时,会出现脂质积累和减少能量产生,这表明肝脏疾病的早期阶段.

科学领域:

肝病学
线粒体生物学
干细胞研究

背景情况:

与代谢功能失调相关的脂肪性肝病 (MASLD) 具有肝细胞线粒体适应脂质受损的特征.
在MASLD中,线粒体功能障碍有助于反应性氧物种 (ROS) 的产生和疾病的进展.
研究患者衍生细胞中的线粒体功能为早期疾病机制提供了见解.

研究的目的:

要确定来自MASLD患者的诱导多能干细胞 (iPSC),是否分化为肝细胞样细胞 (iPSC- Heps),显示线粒体功能障碍.
评估MASLD iPSC-Heps中的脂质积累,线粒体功能和细胞能量状态.
探索PNPLA3基因型在MASLD相关的线粒体变异中的作用.

主要方法:

从10名MASLD患者和10名健康对照患者的IPSC分化为IPSC-Heps.
在基底和palmitate挑战条件下评估线粒体质量和功能.
测量基因表达,氧气消耗,ROS产量和ATP水平.

主要成果:

MASLD iPSC-Heps比对照组积累了更多的脂质.
线粒体含量相似,但MASLD iPSC- Heps 显示使用棕酸盐减少了氧气消耗.
在棕酸盐治疗后,MASLD iPSC- Heps 呈现出增加的 ROS 生产和降低的 ATP 水平.
这些线粒体差异独立于PNPLA3基因型.

结论:

在早期的MASLD中观察到的患者衍生的iPSC-Heps复制线粒体功能障碍.
观察到的线粒体变化之前的进展到脂肪肝炎.
在这个模型中,线粒体功能障碍不仅仅取决于PNPLA3基因型.

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